Background:Opioid analgesics suppress the hypothalamic-pituitary-gonadal axis; consequently, androgen deficiency is common in men treated with opioid analgesics. In animal studies, testosterone displays anti-nociceptive properties and improves pain perception. However, the effects of testosterone replacement on pain perception and quality of life (QOL) in opioid-treated men have not been studied in a randomized-controlled trial.

Objective: To determine whether testosterone replacement improves pain perception and tolerance, and QOL in men with opioid-induced androgen deficiency.

Methods: 84 men (age 18-64 yrs) with opioid-induced androgen deficiency were randomized to 5 gm of transdermal testosterone gel or placebo for 14 weeks. Two weeks post-randomization, dose titration was performed to achieve serum testosterone concentrations between 500 and 1000 ng/dl. The primary outcome was clinical pain(subjective pain perception) that was measured by the Brief Pain Inventory (BPI) questionnaire. Secondary outcomes included Quantitative Sensory Testing (QST) of pain threshold and tolerance; and measures of QOL using the SF-36 questionnaire. All outcomes were measured at baseline and at week 12. Total testosterone was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone was calculated. Statistical comparisons were by Student’s t-tests.

Results: 65 men [testosterone (36), placebo (29)] completed the trial. The two groups were well-matched at study entry. At baseline, mean (SD) age was 49 (±8) yrs, BMI 33 (±7) kg/m², total testosterone 228 (±91) ng/dl and free testosterone 44 (±21) pg/ml. Both total and free serum testosterone levels significantly increased in the testosterone arm. At 12-weeks, men randomized to testosterone showed nominal mean improvements on the pain interference subscale of BPI, but neither this nor overall changes in composite BPI scores were significantly different between the two groups. The men randomized to testosterone experienced significant improvements in pressure pain threshold (p<0.031), mechanical pain intensity (p=0.049) and cold presser pain after-sensations (p=0.08). The testosterone-treated group also showed a trend toward improvement in aspects of role limitation due to emotional problems as measured by MOS-SF-36.

Conclusion: Testosterone administration in men with opioid-induced androgen deficiency for 12-weeks was associated with a greater reduction in several measures of pain sensitivity during QST. As improvements in laboratory-based indices of central sensitization often precede improvement in clinical pain, trials of longer duration might be necessary to definitively address the anti-nociceptive role of testosterone.